Interactions between Calcium and Alpha-Synuclein in Neurodegeneration

In Parkinson’s disease and some atypical Parkinson’s syndromes, aggregation of the α-synuclein protein (α-syn) has been linked to neurodegeneration. Many triggers for pathological α-syn aggregation have been identified, including port-translational modifications, oxidative stress and raised metal ions, such as Ca(2+). Recently, it has been found using cell culture models that transient increases of intracellular Ca(2+) induce cytoplasmic α-syn aggregates. Ca(2+)-dependent α-syn aggregation could be blocked by the Ca(2+) buffering agent, BAPTA-AM, or by the Ca(2+) channel blocker, Trimethadione. Furthermore, a greater proportion of cells positive for aggregates occurred when both raised Ca(2+) and oxidative stress were combined, indicating that Ca(2+) and oxidative stress cooperatively promote α-syn aggregation. Current on-going work using a unilateral mouse lesion model of Parkinson’s disease shows a greater proportion of calbindin-positive neurons survive the lesion, with intracellular α-syn aggregates almost exclusively occurring in calbindin-negative neurons. These and other recent findings are reviewed in the context of neurodegenerative pathologies and suggest an association between raised Ca(2+), α-syn aggregation and neurotoxicity.